March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Maternal Uniparental Isodisomy Of Chromosome 6 Reveals A Tulp1 Mutation As A Novel Cause Of Cone Dysfunction
Author Affiliations & Notes
  • Susanne Roosing
    Department of Human Genetics, Department of Ophthalmology,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Ingeborgh L. van den Born
    The Rotterdam Eye Hospital, Rotterdam, The Netherlands
  • Alberta A. Thiadens
    Department of Human Genetics, Department of Ophthalmology,
    Erasmus Medical Centre, Rotterdam, The Netherlands
  • Carel B. Hoyng
    Department of Ophthalmology, Department of Epidemiology,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Frans P. Cremers
    Department of Human Genetics, Department of Ophthalmology,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, The Netherlands
  • Caroline C. Klaver
    Department of Human Genetics, Department of Ophthalmology,
    Department of Ophthalmology, Department of Epidemiology,
    Erasmus Medical Centre, Rotterdam, The Netherlands
  • Anneke I. den Hollander
    Department of Human Genetics, Department of Ophthalmology,
    Department of Ophthalmology, Department of Epidemiology,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Footnotes
    Commercial Relationships  Susanne Roosing, None; Ingeborgh L. van den Born, None; Alberta A. Thiadens, None; Carel B. Hoyng, None; Frans P. Cremers, None; Caroline C. Klaver, None; Anneke I. den Hollander, None
  • Footnotes
    Support  BR-GE-0510-0489-RAD
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 4555. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Susanne Roosing, Ingeborgh L. van den Born, Alberta A. Thiadens, Carel B. Hoyng, Frans P. Cremers, Caroline C. Klaver, Anneke I. den Hollander; Maternal Uniparental Isodisomy Of Chromosome 6 Reveals A Tulp1 Mutation As A Novel Cause Of Cone Dysfunction. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4555.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: : The majority of the genetic causes of autosomal recessive cone dystrophy (arCD) is currently unknown. Therefore, we employed a high-resolution homozygosity mapping approach in a cohort of arCD patients to identify new genes for arCD.

Methods: : A cohort of 83 arCD patients was genotyped with Affymetrix 5.0 SNP microarrays. Homozygous regions in the patients’ genomes were determined with Partek Genomics Solution software. One patient showed homozygosity of SNPs across chromosome 6. To test the possibility of uniparental isodisomy (UPD), segregation analysis was performed in family members of this patient using several microsatellite markers on chromosome 6. Direct sequencing of all retinal disease genes on chromosome 6 (ELOVL4, EYS, IMPG1, LCA5, RDS and TULP1) followed, and revealed a pathogenic TULP1 mutation in this patient. A cohort of 159 arCD patients was screened for this particular mutation using the restriction enzyme HhaI.Ophthalmic examination of these patients included electroretinography, perimetry, optical coherence tomography, fundus autofluorescence, and fundus photography.

Results: : Segregation analysis with microsatellite markers confirmed maternal UPD in this patient. Screening of TULP1 revealed a novel homozygous missense mutation (p.Arg420Ser), while no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain, and is predicted to be pathogenic using several prediction programs. The mutation was not found in 159 ethnically matched controls, nor in our in-house exome (n=383) database and online exome and SNP databases. Screening of 159 cone dystrophy individuals identified the same mutation in an unrelated CD patient. Both patients carried the homozygous p.Arg420Ser mutation and displayed a cone dystrophy characterized by deterioration of visual acuity, a reduced cone ERG, and central sensitivity loss on perimetry.

Conclusions: : Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of arCD. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease.

Keywords: retina • degenerations/dystrophies • candidate gene analysis 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×